An important long-term goal in the development of strategies to treat complications associated with diabetes such as, cerebrovascular disease and stroke, is to understand the mechanisms that regulate the structure of cerebral blood vessels;a process termed "cerebrovascular remodeling." Endothelin-1 (ET-1), a mitogen, is chronically elevated in diabetes. While it is known that ETA receptor activation causes vasoconstriction and VSMC growth, and that the relative ratio of ET receptors (density of ETA and ETB on VSMCs to ETB on endothelial cells) dictates the contractile effects of ET-1;the importance of endothelial ETB receptors in modulating cell growth and vascular structure, and the temporal changes that occur in ET receptor ratios in the cerebral vasculature during diabetes progression are unclear. Diabetic conditions such as elevated glucose and insulin also stimulate expression and activity of matrix metalloproteinases (MMPs), a family of proteases that are critical for vascular remodeling. However, the potential role of ET-1 in regulation of high glucose-stimulated MMP activity, and especially to cerebrovascular remodeling in Type 2 diabetes is unknown. Our central hypothesis is that diabetes-induced changes in the ET system promote hypertrophic remodeling of cerebral microvessels via MMP-mediated activation of cell surface-bound growth signals. To better understand the mechanisms by which diabetes influences cerebrovascular remodeling, Specific Aims will test the subhypotheses that: 1) diabetes stimulates the cerebral microvascular ET system by inducing ET-1 synthesis and increasing the ETA/ETB receptor ratio via down-regulation of vasculoprotective endothelial ETB receptors. Our working model is that endothelial ETB receptors are vasculoprotective and that pharmacological blockade, genetic inhibition and/or diabetes-induced down-regulation of this receptor subtype exacerbates cerebrovascular remodeling in Goto-Kakizaki (GK) rats, a model of Type 2 diabetes. 2) ET-1-mediated stimulation of MMP activity and sequential transactivation of membrane-bound growth factors causes hypertrophic remodeling of cerebral microvessels in diabetes. Our working model is that ET-1, through stimulation of MMP expression and activity, disrupts the integrity of vascular structures to facilitate VSMC proliferation, and enhances epidermal growth factor receptor (EGFR) transactivation, leading to pathological remodeling in the cerebrovasculature in diabetes. Collectively, these studies will contribute to our understanding of the pathophysiological basis of cerebrovascular complications associated with diabetes and development of cerebrovascular protection strategies to retard the progression, delay the onset and even possibly prevent cerebrovascular disease and stroke in diabetes.